Comparison of Tirilazad Mesylate (U-74006F) and Methyl Prednisolone Sodium Succinate Treatments in Experimental Allergic Encephalomyelitis in the Guinea Pig

Abstract

The effects of the non-glucocortioid 21-aminosteroid, tirilazad mesylate (U-74006F), on MRI and clinical findings in guinea pigs with experimental allergic encephalomyelitis were compared to treatment with methylprednisolone sodium succinate (MPSS). A dose response experiment for U-74006F was performed 1, 3 and 10 mg/kg/day IP on day 0–12 after immunization. Additionally, the 3 mg/kg/day IP dose was extended to 24 and 35 days. MPSS was given in three different protocols at doses ranging from 0.8 to 3.2 mg/kg/day. Abnormalities in T2-weighted images were assessed as measures of edema and inflammation and gadolinium-DTPA enhanced TI-weighted images were used to determine blood-brain barrier integrity. U-74006F improved the clinical status at doses of 3 and 10 mg/kg. For example, maximum clinical score was halved at 10 mg/kg/day (P < 0.01). The presence of gadolinium-DTPA in the parenchyma was also decreased at 3 and 10 mg/kg/day U-74006F although maximum MRI scores were decreased only in the 10 mg/kg U-74006F group. Clinical disease suppression seen with 3 mg/kg treatment on days 0–12 reverted to control at > 24 days of dosing. MPSS treatment considerably worsened the clinical outcome of EAE Mean clinical scores for vehicle and the highest MPSS dose were 0.94 ± 0.66 versus 2.64 ± 1.49 (P < 0.05). The combination of decreased T2-weighted abnormalities, clinical signs and gadolinium-DTPA permeation in the U-74006F treated animals suggested protection of the blood–brain barrier without the severe glucocorticoid effects associated with steroid therapy.